1. Field of the Invention
The present invention relates to new use of Lactobacillus isolates, in particular, to the technical field of treatments for type II diabetes.
2. Description of the Prior Art
Diabetes Mellitus is a metabolism disease of many pathogens. It is a disease caused by extensive metabolism dysfunction induced by the defects produced in the secretion or action of insulin. The main feature of diabetes consists of constant chronic high blood sugar, as well as metabolic disorder of protein, lipid, water, electrolyte and the like.
Clinically, diabetes is classified mainly into two types:
Type 1: Insulin-dependent diabetic mellitus (IDDM), occurs mostly before the age of 30 as such been named as “Juvenile-Onset diabetes”, but actually it may occur at any age. Type 1 diabetes is an autoimmune disease in which the immune system itself attacks β cells in the islets of Langerhans in the pancreas. Its cause is involved with personal genetics, virus infection, or damage of toxic substance on β cells of the pancreas, antibodies against β cells produced by autoimmunology, and attacking on β cells by cellular immune action. Eventually, the pancreas of the subject cannot secrete insulin normally and becomes extremely susceptible to toketoacidosis and in need of treatment of insulin injection.
Type 2: Non-insulin dependent diabetic mellitus (NIDDM), occurs mostly after the age of 40 years. Most patients with NIDDM are overweight and therefore this type has been called “maturity-onset diabetes” in the past. However, it may occur in young men and familial occurrence is often found. This type of diabetes consists of more than 95% of total diabetes population in Taiwan. This type of diabetes is caused by defects in insulin secretion, and insulin resistance; in which, though decrease of insulin secretion in some patients may be observed, most patients have acceptable ability to produce insulin. Therefore, its treatment depends largely on dietary control and oral administration of blood glucose-lowering drugs to control blood glucose level and does not need insulin injection immediately. In addition, most patients may be accompanied by insulin resistance. Formation of insulin resistance comes primarily from the excess secretion of insulin (hyperinsulinemia) by the β cells in the islets of Langerhans in the pancreas, which causes decreased insulin sensitivity of peripheral tissues such as skeleton muscles, adipose tissues, liver and the like, thereby diminishes the utilization of glucose in these tissues, and hence induces the phenomenon of high blood sugar. Progression of this type is slow, no typical diabetes symptom emerges at the early stage and hence it is not easy to detect. It is accompanied usually by chronic complications such as diabetic pathogenic change of large vessels (for example, cardiomuscular infarction and brain stroke), small vessels (for example in kidney, retina and nerve) and the like.
In addition, subjects of type 2 diabetes are accompanied usually with abnormal lipid metabolic conditions, such as increasing of triglyceride (TG) concentration, lowering of high density lipoprotein cholesterol (HDL-C) concentration and increasing of low density lipoprotein cholesterol (LDL-C) concentration in the plasma. This syndrome may incur in type 2 diabetes subjects with risk of cardiovascular diseases. Further, it has been pointed out that serious diabetes subjects might diminish their ability to clear blood lipid in the liver. When triglyceride and low density lipoprotein cholesterol has been accumulated continuously to some extent, pathological change of liver cells may occur to form non-alcoholic fatty liver and affect the liver function severely.
Other than the administration of insulin, two additional ways for treating diabetes consists of non-drug and drug treatments. Non-drug treatment resides mainly on dietary regulation and sport. Whereas in the aspect of drug treatment, its primary object involves rising the deficiency of insulin, regulating down the high blood sugar after meal, improving insulin resistance and the like. At present, drugs used to treat diabetes may include:
(1) Sulfonylurea: The main mechanism of this type of drug is to promote the secretion of insulin from the pancreas, especially to enhance the stimulation of pancreatic β cell against glucose so as to release insulin; commonly used sulfonylurea blood glucose-lowering drug includes glibenclamide (trade name: Euglucon), glipizide (trade name: Minidiab) and gliclazide (trade name: Diamicron). However, in addition to its side-effects, such as rash and pruitus, its application to subject is also limited. For example, one that has severe liver and kidney dysfunction, pregnant women and nurses, and one that has severe sensitivity to sulfonylurea drug, are all not suitable to use this type of blood sugar-lowering drug.
(2) α-Glucosidase inhibitor: The main mechanism of this type of drug is to inhibit activities of pancreatic α-amylase and intra-intestinal α-glucosidase, and further inhibit the decomposition and absorption of carbohydrate in the intestinal tract. This type of drug can effectively lower the blood sugar after meal and insulin concentration, with side-effect of abdominal distention or occasional diarrhea, bellyache and nausea.
(3) Thiazolidinedione derivatives: The main action of this type of drug is to increase the activity of peroxisome proliferator-activated receptor (PPAR)-gamma in the cell nucleus, and further enhance the effect of insulin, such that glucose transfer protein GLUT2 and GLUT4 in the cell is increased so as to transport glucose into the cell for use. Commonly used one in clinic includes troglitazone (trade name: Rezulin), rosiglitazone (trade name: Avandia), pioglitazone (trade name: Actos) and the like. Among these, troglitazone induces lethal liver-toxicity, and therefore, it has been prohibited to be used two months after marketing in England in October 1997. Furthermore, in the USA, thiazolidinedione derivatives has been issued an order to withdraw comprehensively and to be forbid its use.
(4) Biguanides: This type of drug belongs to guanidine derivative. At present, biguanide blood sugar-lowering drug now is mainly metformin. This type of drug does not itself stimulate the secretion of insulin. Main mechanism in controlling blood sugar consists of following five points: a. Inhibiting appetite, and therefore is used preferably for obese type 2 diabetes patients to reduce their appetites, lower their body weight and further improve the peripheral action of insulin; b. Retarding the absorption of glucose by the intestinal tract; c. Promoting the anaerobic decomposition of glucose in the intestinal tract, and further increase the utilization of glucose in the intestinal tract, however, this may produce excess lactate that is susceptible to cause lactic acidosis; d. Enhancing the action of insulin in the liver, thereby inhibiting the neogenesis of glucose in the liver, and reduce the release of glucose from the liver; e. Promoting glucose transfer protein GLUT4 stored in the cell to move to the cell surface and to participate in the action of glucose transport, thereby increasing significantly the amount of glucose transfer protein on the cell surface. This type of blood sugar-lowering drug has some side-effects such as gastrointestinal discomfort in the first administration, for example anorexia, nausea, omitting, diarrhea and the like. A few may experience a skin rash, and after long-term use, inactivation phenomenon.
Probiotics are translated into many other names in Chinese and are defined by Food and Agriculture Organization of the United Nations (FAO) as live microorganisms and contains huge amounts of bacteria which can exert benefits on the host and help maintain their health. Majority of probiotics are lactic acid bacteria which can proliferate in the gut and produce lactic acid, acetic acid and short-chain fatty acids and exert a number of physiological functions. Among which, functions related to metabolic syndrome are described as follows: (1) Prevent diarrhea and constipation. Lactic acid and acetic acid can prevent invasion of foreign pathogens and proliferation of the spoilage bacteria, promote and maintain normal bowl movement and thus prevent diarrhea and constipation. (2) Regulate blood glucose level. Previous studies indicated that lactic acid bacteria can reduce blood glucose level and providing rats with sour milk daily containing probiotics for 8 weeks significantly reduces blood glucose level, glycosylated hemoglobin, OGTT and insulin levels in these rats. Administration of fermented milk containing probiotics also notably decreases blood glucose level in rats with diabetes induced by injection of streptozotocin (STZ). (3) Lower cholesterol and regulate blood lipids. Lactic acid bacteria may reduce cholesterol level by various mechanisms. The hydrolase activity of bile salt of the lactic acid bacteria allows cholesterol to be processed into conjugated bile salt during metabolism. When the bile salt binding activity increases, binding of cholesterol with conjugated bile salt results in co-precipitation and more cholesterol is precipitated and consequently contributes to the effect of cholesterol reduction. On the other hand, lactic acid bacteria can bond with cholesterol or even undergo of absorbed cholesterol and generate substances which are required by the cells. Among which, Lactobacillus has been shown to have better efficacy in cholesterol reduction. (4) Regulate blood pressure. Blood pressure-lowering substances are found in some fermented milk products, which is the best example of application of non-live probiotics in non-intestinal tract diseases. L. helveticus degrade lactoprotein during the process of fermentation and produce a number of peptides, among which VPP (Val-Pro-Pro) and IPP (Ile-Pro-Pro) can inhibit the activity of ACE. After intake of L. helveticus, the blood pressure of patients with high blood pressure is significantly lowered when compared with that before intake. (5) Lactobacillus can process free radicals through SOD or high concentration of Mn ions or reduce the toxicity of free radicals and H2O2 via glutathione. (6) Probiotics can reduce the expression of cytokines during the course of complicated inflammation. Mattar example: probiotics can increase the expression of Mucin 2 glycoprotein (MUC-2) in Caco-2 and reduce inflammation. In addition, studies conducted in cells indicated Lactobacillus plantarum 10hk2 can notably reduce the levels of inflammation-inducing cytokines such as interleukin-1β(IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) and increase the level of the anti-inflammatory cytokine IL-10. (7) Certain bacteria in human intestinal tract such as Lactobacillus and Bifidobacterium can regulate symbiotic intestinal flora in the intestine through the intake of probiotics or supply nutrients.
Several literature or patents have suggested that feeding the diabetic rats with Lactobacillus can effectively prevent diabetes and lower blood glucose levels. Nonetheless, these published literature or patents on prevention of diabetes by Lactobacillus are limited to the controlling of blood glucose levels, body weight, blood lipid levels and cholesterol levels, and no further improvements are reported in prevention of other complications of diabetes such as inflammatory responses and declined liver function. Prior applications filed by the inventor of present invention indicates that Lactobacillus reuteri GMNL-89 can inhibit inflammatory responses (U.S. Pat. No. 7,901,926) and in U.S. Pat. No. 8,298,526, Lactobacillus reuteri GMNL-89 was found to efficiently improve the symptoms of type I diabetes under the disease model of type 1 diabetes. However, up to date, whether probiotics can effectively improve the symptoms of type 2 diabetes in the disease model of type 2 diabetes remains unclear.